Process for production of 2-substituted benzo[b]thiophene

ABSTRACT

The present invention provides a process for producing a 2-substituted benzo[b]thiophene, which is characterized by reacting a substituted or unsubstituted 2-halogenobenzaldehyde with sulfur and a compound represented by general formula (1) 
     
         H.sub.i S.sub.j M.sub.k                                    (1) 
    
     (wherein M represents an alkali metal; i represents an integer of 0 or 1; j represents an integer of 1 or more; and k represents an integer of 1-2 with a proviso that i+k=2), or with a compound of general formula (1) wherein j is 2 or more, in the presence of an aprotic polar solvent, and then reacting the reaction mixture with a compound represented by general formula (2) 
     
         XCH.sub.2 R                                                (2) 
    
     (wherein X represents a halogen atom; and R represents an acyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted arylcarbonyl group or a cyano group) to give rise to intramolecular ring closure. 
     The present process uses no unstable raw materials; enables production of an intended product in a simple operation at a high yield; and is very effective as a process for industrial production of 2-substituted benzo[b]thiophene.

This application is a 371 PCT/JP94/01578 Aug. 26, 1994.

1. Technical Field

The present invention relates to a process for industrially producing a2-substituted benzo[b]thiophene which is useful, for example, as anintermediate for drug synthesis.

2. Background Art

For the production of 2-substituted benzo[b]thiophene, there is proposeda process which comprises reacting benzo[b]thiophene with a strong basesuch as butyl lithium or the like and reacting the reaction mixture withan acid chloride such as acetyl chloride or the like to obtain a2-acylbenzo[b]thiophene [J. Chem. Soc., Chem. Comun., 3447 (1971)].

The above process, however, has problems in that the use of butyllithium (which is difficult to handle) in the reaction makes theindustrial operation difficult and moreover benzo[b]thiophene and butyllithium both used as raw materials are expensive.

A process is also known which comprises reacting 2-mercaptobenzaldehydewith an α-haloketone such a s chloroacetone or the like to obtain a2-acylbenzo[b]thiophene (Comptes rendus, Vol. 234,736).

This process, however, has problems in that the industrial synthesis of2-mercaptobenzaldehyde used as a raw material is difficult and moreoverthis compound is unstable and needs careful handling.

The task of the present invention is to provide a process forindustrially producing a 2-substituted benzo[b]thiophene inexpensively.

DISCLOSURE OF THE INVENTION

The present inventors made a study on the process for industrialproduction of 2-substituted benzo[b]thiophene. As a result, the presentinventors unexpectedly found out that the conventional problems could besolved and a 2-substituted benzo[b]thiophene could easily be produced byreacting a 2-halogenobenzaldehyde of high commercial availability with aparticular inorganic sulfur compound and reacting the reaction mixturewith a compound represented by general formula (2) (shown below) to giverise to intramolecular ring closure. The present invention has beencompleted based on the above finding.

The present invention provides a process for producing a 2-substitutedbenzo[b]thiophene, which is characterized by reacting a substituted orunsubstituted 2-halogenobenzaldehyde with sulfur and a compoundrepresented by general formula (1)

    H.sub.i S.sub.j M.sub.k                                    (1)

(wherein M represents an alkali metal; i represents an integer of 0 or1; j represents an integer of 1 or more; and k represents an integer of1-2 with a proviso that i+k=2), or with a compound of general formula(1) wherein j is 2 or more, in the presence of an aprotic polar solvent,and then reacting the reaction mixture with a compound represented bygeneral formula (2)

    XCH.sub.2 R                                                (2)

(wherein X represents a halogen atom; and R represents an acyl group, asubstituted or unsubstituted alkoxycarbonyl group, a substituted orunsubstituted arylcarbonyl group or a cyano group) to give rise tointramolecular ring closure.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in detail below.

The present invention comprises a first reaction of reacting asubstituted or unsubstituted 2-halogenobenzaldehyde (which mayhereinafter be referred to simply as 2-halogenobenzaldehydes) withsulfur and a compound represented by general formula (1), or with acompound of general formula (1) wherein j is 2 or more, in the presenceof an aprotic polar solvent to obtain a reaction mixture, and a secondreaction of reacting the reaction mixture obtained in the firstreaction, with a compound represented by general formula (2) to giverise to intramolecular ring closure to obtain a 2-substituted benzo[b]thiophene.

Description is made firstly on the aprotic polar solvent used throughoutthe first and second reactions of the present invention.

Specific examples of the aprotic polar solvent used throughout the firstand second reactions of the present invention are N-methylpyrrolidone,N-octylpyrrolidone, 1,3-dimethylimidazolidinone, diethylacetamide,dimethylacetamide, dimethylformamide, dimethyl sulfoxide, sulfolane,tetramethylurea, hexamethylphosphoric triamide andN-methyl-N-phenylformamide. These aprotic polar solvents can be used inany combination of two or more of them.

In the present process there may be used, as the reaction solvent, amixed solvent consisting of the aprotic polar solvent and anothersolvent which is inactive in the reactions. Specific examples of anothersolvent are aromatic hydrocarbon solvents such a s benzene, toluene,xylene, chlorobenzene and dichlorobenzene.

In the present process, the amount of the solvent used is sufficient ifit can ensure stirring. The amount is ordinarily 100-3,000 ml per moleof the 2-halogenobenzaldehydes.

Next, description is made on the first reaction of the present process.

The 2-halogenobenzaldehydes usable in the first reaction includebenzaldehydes whose 2-position is substituted with a halogen atom suchas fluorine atom, chlorine atom, bromine atom, iodine atom or the like(hereinafter, halogen atom has the same definition) and at least oneposition of the 3-to 6-positions of these benzaldehydes may besubstituted with unrestricted group(s) such as halogen atom(s), nitrogroup(s), cyano group(s) and the like.

Of the compounds of general formula (1) used in the first reaction, thecompound wherein j is 1, i.e. the monosulfur compound can specificallybe exemplified by potassium sulfide, sodium sulfide, potassiumhydrosulfide and sodium hydrosulfide; and the compound wherein j is 2 ormore, i.e. the polysulfur compound can specifically be exemplified bysodium polysulfides and potassium polysulfides, more specifically bysodium disulfide, sodium trisulfide, sodium tetrasulfide, sodiumpentasulfide, potassium disulfide, potassium trisulfide, potassiumtetrasulfide and potassium pentasulfide. A combination example of sulfurand the compound represented by general formula (1) is a combination ofsulfur and a monosulfur compound or a polysulfur compound.

It is possible to use, as necessary, two or more of the compoundsrepresented by general formula (1).

In the first reaction, when the compound of general formula (1) is usedin combination with sulfur, the amount of said compound used isordinarily 0.5-10 moles, preferably 1-3.5 moles per mole of the2-halogenobenzaldehydes, and the amount of sulfur used is ordinarily 10moles or less, preferably 3.5 moles or less per mole of the2-halogenobenzaldehydes. When no sulfur is used and there is used onlythe compound of general formula (1) wherein j is 2 or more, the amountof said compound used is ordinarily 0.5-10 moles, preferably 1-3.5 molesper mole of the 2-halogenobenzaldehydes.

When the compound of general formula (1) is used in combination withsulfur, it is preferable that the compound of general formula (1) andsulfur are stirred beforehand in an aprotic polar solvent in the rangefrom room temperature to 50° C. for 0.5-3 hours.

In the first reaction, it is possible to employ any order of adding the2-halogenobenzaldehydes, and the compound of general formula (1) andsulfur or only the compound of general formula (1) wherein j is 2 ormore. However, the pattern of adding the 2-halogenobenzaldehydes gives amore favorable result.

In the first reaction, the reaction temperature is any temperature inthe range from 0° C. to the boiling point of the solvent, preferably inthe range of 0°-80° C. While the completion of the reaction can beconfirmed by examining the disappearance of the 2-halogenobenzaldehydesby gas chromatography, the reaction time is generally 3-24 hours.

Subsequently, description is made on the second reaction of the presentprocess.

The compound represented by general formula (2), used in the secondreaction can be exemplified by α-halocarbonyl compounds andhalogenonitrile compounds. The α-halocarbonyl compounds are specificallymonohalogenoacetone compounds such as chloroacetone, bromoacetone andthe like; halogenoalkanoic acid ester compounds such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, amyl, isoamyl, tert-amyl, sec-isoamyl, hexyl orisohexyl esters of monochloroacetic acid, monobromoacetic acid,monoiodoacetic acid, monochloropropionic acid, monobromopropionic acid,monoiodopropionic acid, monochlorobutanoic acid, monobromobutanoic acid,monoiodobutanoic acid, monochloropentanoic acid, monobromopentanoicacid, monoiodopentanoic acid, monochlorohexanoic acid, monobromohexanoicacid and monoiodohexanoic acid; and phenacyl halide compounds(arylcarbonylmethyl halide compounds) such as 2-chloroacetophenone,2-chloroacetonaphthone, 2-chloro-2'-methylacetophenone,2-bromoacetophenone, 2-bromoacetonaphthone, 2-bromo-2'-methylacetophenone, 2iodoacetophenone, 2 -iodoacetonaphthone,2-iodo-2'-methylacetophenone and the like. The halogenonitrile compoundsare specifically chloroacetonitrile, bromoacetonitrile,iodoacetonitrile, chloropropionitrile, bromopropionitrile,chlorobutyronitrile, bromobutyronitrile and the like.

In the second reaction, the amount of the compound of general formula(2) used is generally 0.5-10 moles, preferably 1-2 moles per mole of the2-halogenobenzaldehydes.

The second reaction proceeds in any order of adding the compound ofgeneral formula (2) and the reaction mixture formed in the firstreaction. However, in view of the easiness of the operation, etc.,generally the compound of general formula (2) is added into the vesselof the first reaction containing the reaction mixture obtained in thefirst reaction, and the first reaction and the second reaction areconducted continuously in the same vessel.

In the second reaction, the temperature at which the compound of generalformula (2) is allowed to act on the reaction mixture formed in thefirst reaction is not specified. However, since the reaction is anexothermic reaction, the temperature is preferably kept in the range of0°-80° C. by cooling as necessary. The time in which the compound isallowed to act, is generally 1-16 hours to achieve the object althoughthe time varies depending upon various factors such as raw materials,solvent, reaction temperature, etc. used.

The rate of the intramolecular ring closure reaction taking placesubsequently to the substitution reaction is small in some casesdepending upon the kind of the compound of general formula (2) used inthe second reaction. In such cases, addition of a strong base such asmetal alcoholate (e.g. sodium methylate, sodium ethylate or potassiummethylate) can increase said rate to quickly obtain an intended ringclosure product, i.e. a 2-substituted benzo[b]thiophene.

As a result, the time required in the present process throughout thefirst reaction and the second reaction is generally 4-43 hours althoughit varies depending upon the compounds, reaction conditions, etc. used.

In the present process, the intended product obtained may berecrystallized from an appropriate solvent such as cyclohexane,alcohol-water mixture or the like or subjected to distillation to obtaina 2-substituted benzo[b]thiophene of higher purity.

When the 2-position substituent of the obtained 2-substitutedbenzo[b]thiophene is an alkoxycarbonyl group or a cyano group, thecompound is hydrolyzed by an ordinary method, wherebybenzo[b]thiophene-2-carboxylic acid can easily be obtained. Thisbenzo[b]thiophene-2-carboxylic acid can easily be converted intobenzo[b]thiophene having no substituent at the 2-position by subjectingto a decarboxylation treatment in a quinoline solvent in the presence ofa copper catalyst at about 200°-300° C. When the 2-position substituentis a cyano group, the 2-substituted benzo[b]thiophene is hydrolyzedunder appropriately altered conditions, wherebybenzo[b]thiophene-2-carboxamide can be produced.

EXAMPLES

The present invention is described more specifically below by way ofExamples.

EXAMPLES 1-2

Into a 200-ml four-necked flask equipped with a stirrer, a thermometerand a reflux condenser were fed 11.7 g (150 mM) of anhydrous sodiumsulfide, 3.2 g (100 mM) of sulfur and 100 ml of N-methylpyrrolidone. Themixture was stirred at room temperature for 1 hour. To the mixture wasdropwise added 100 mM of a 2-halogenobenzaldehyde shown in Table 1. Themixture was stirred at room temperature for 12 hours. To the reactionmixture being water-cooled was dropwise added 120 mM of a compound ofgeneral formula (2) shown in Table 1. The mixture was stirred at roomtemperature for 6 hours to give rise to a reaction. After the completionof the reaction, 100 ml of diethyl ether and 100 ml of water were addedto the reaction mixture. Further, an aqueous sodium hydroxide solutionwas added to allow the aqueous layer to have a pH of above 11. Then,extraction with diethyl ether was conducted. The resulting diethyl etherlayer was water-washed twice and concentrated under reduced pressure toremove diethyl ether to obtain a 2-substituted benzo[b]thiophene. The2-halogenobenzaldehydes and compound of general formula (2) used in EachExample, the product and the yield are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                      Compound                                                    Example                                                                            2-Halogeno-  of general               Yield*                             No.  benzaldehydes                                                                              formula (2)                                                                           Product          (%)                                __________________________________________________________________________          ##STR1##    ClCH.sub.2 COPh                                                                        ##STR2##        71                                 2                                                                                   ##STR3##    ClCH.sub.2 COCH.sub.3                                                                  ##STR4##        95                                 __________________________________________________________________________     *Obtained by gas chromatography.                                         

In the above table, Ph refers to phenyl group.

Example 3

Into a 200-ml four-necked flask equipped with a stirrer, a thermometerand a reflux condenser were fed 14.1 g (0.18 mole) of anhydrous sodiumsulfide, 5.8 g (0.18 mole) of sulfur and 45 ml of dimethylformamide. Themixture was stirred at room temperature. Heat generation occurred andthe mixture temperature increased to 45° C. After the completion of theheat generation, 21.1 g (0.15 mole) of 2-chlorobenzaldehyde was dropwiseadded in 10 minutes at 70°-75° C. with slight heating. The mixture wasstirred at the same temperature for 4 hours. The reaction mixture wascooled to room temperature. To the mixture being stirred was dropwiseadded 16.3 g (0.15 mole) of methyl chloroacetate in 10 minutes underspontaneous heat generation. The mixture was stirred at 55°-60° C. for1.5 hours. 8.1 g (0.15 mole) of sodium methoxide was added at the sametemperature, followed by stirring for 30 minutes. The reaction mixturewas analyzed by gas chromatography, which indicated the formation ofmethyl benzo[b]thiophene-2-carboxylate in an amount of 86% by arealratio. The reaction mixture was stirred for a further 1 hour. 40 ml ofwater and 6 g of 48% sodium hydroxide were added and the mixture wasstirred at 95° C. for 1.5 hours to give rise to hydrolysis. After thecompletion of the reaction, dilution with 100 ml of water was conducted.100 ml of toluene was added and extraction was conducted at 75° C. toremove neutral components. The aqueous layer was placed in a 1-litterbeaker. Thereto was dropwise added 22.1 g (0.21 mole) of 95% sulfuricacid with stirring. The resulting crystals were collected by filtrationand dried to obtain 17.6 g of crude benzo[b]thiophene-2-carboxylic acid.This product was washed with toluene and redried to obtain 17.1 g ofbenzo[b]thiophene-2-carboxylic acid. The yield was 64.0% and the puritywas 99.7%.

Example 4

A reaction up to the formation of a ring closure product was conductedin the same manner as in Example 3 except that 11.3 g (0.15 mole) ofchloroactonitrile was used in place of methyl chloroacetate, the amountof sodium methoxide used was changed to 4.1 g and, after the addition ofsodium methoxide, stirring was conducted at 70° C. for 3 hours tocomplete the reaction. The reaction mixture was placed in 400 ml ofwater, and extraction with 300 ml of toluene was conducted. The toluenelayer was washed twice with 400 ml of water. The organic layer was driedwith anhydrous sodium sulfate and concentrated to obtain 13.2 g of2-cyanobenzo[b]thiophene. Yield: 55.3% )

Industrial Applicability

The present invention provides a novel process for producing a2-substituted benzo[b]thiophene, which is characterized by reacting2-halogenobenzaldehydes of high commercial availability with a compoundrepresented by general formula (1) and sulfur or with a compoundrepresented by general formula (1) wherein j is 2 or more, and thenreacting the reaction mixture with a compound represented by generalformula (2) to give rise to intramolecular ring closure.

Therefore, the present process involves no handling of any raw materialand intermediate which are unstable and difficult to handleindustrially; can produce a 2-substituted benzo[b]thiophene from rawmaterials of high availability and low cost, in a simple operation at ahigh yield; and is very effective as a process for industrial productionof 2-substituted benzo[b]thiophene.

We claim:
 1. A process for producing a 2-substituted benzothiophene,which is characterized by reacting a substituted or unsubstituted2-halogenobenzaldehyde with sulfur and a compound represented by generalformula (1)

    H.sub.i S.sub.j M.sub.k                                    ( 1)

(wherein M represents an alkali metal; i represents an integer of 0 or1; j represents an integer of 1 or more; and k represents an integer of1-2 with a proviso that i+k=2), or with a compound of general formula(1) wherein j is 2 or more, in the presence of an aprotic polar solvent,and then reacting the reaction mixture with a compound represented bygeneral formula (2)

    XCH.sub.2 R                                                (2)

(wherein X represents a halogen atom; and R represents an acyl group, asubstituted or unsubstituted alkoxycarbonyl group, a substituted orunsubstituted arylcarbonyl group or a cyano group) to give rise tointramolecular ring closure.